Targeting of deregulated protein kinases has proven effective for multiple cancers types. Using high-throughput mutational profiling of kinase genes, we previously identified somatic mutations in Mixed Lineage Kinase 4 (MLK4) in colorectal tumors (CRC) (1). MLK4 belongs to the family of MLK serine-threonine kinases thought to activate multiple intracellular signaling pathways. They are characterized by an amino-terminal SRC-homology domain (SH3), followed sequentially by a kinase domain, a leucine-zipper region and a Cdc42/Rac Interactive Binding (CRIB) motif The carboxyl terminus of all MLKs is proline-rich but diverge significantly among different members of the family, indicating that these regions might serve different regulatory functions. The discovery of MLK4 somatic mutations in CRCs suggests that this kinase may be relevant for tumour initiation and development. Nothing is presently known about the biochemical and cellular properties of MLK4 in normal and neoplastic cells.